Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of >2 years of follow-up.

BackgroundNovel second-line treatments are needed for patients with advanced urothelial cancer (UC). Interim analysis of the phase III KEYNOTE-045 study showed a superior overall survival (OS) benefit of pembrolizumab, a programmed death 1 inhibitor, versus chemotherapy in patients with advanced UC that progressed on platinum-based chemotherapy. Here we report the long-term safety and efficacy outcomes of KEYNOTE-045.Patients and methodsAdult patients with histologically/cytologically confirmed UC whose disease progressed after first-line, platinum-containing chemotherapy were enrolled. Patients were randomly assigned 1 : 1 to receive pembrolizumab [200 mg every 3 weeks (Q3W)] or investigator's choice of paclitaxel (175 mg/m2 Q3W), docetaxel (75 mg/m2 Q3W), or vinflunine (320 mg/m2 Q3W). Primary end points were OS and progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) by blinded independent central radiology review (BICR). A key secondary end point was objective response rate per RECIST v1.1 by BICR.ResultsA total of 542 patients were enrolled (pembrolizumab, n = 270; chemotherapy, n = 272). Median follow-up as of 26 October 2017 was 27.7 months. Median 1- and 2-year OS rates were higher with pembrolizumab (44.2% and 26.9%, respectively) than chemotherapy (29.8% and 14.3%, respectively). PFS rates did not differ between treatment arms; however, 1- and 2-year PFS rates were higher with pembrolizumab. The objective response rate was also higher with pembrolizumab (21.1% versus 11.0%). Median duration of response to pembrolizumab was not reached (range 1.6+ to 30.0+ months) versus chemotherapy (4.4 months; range 1.4+ to 29.9+ months). Pembrolizumab had lower rates of any grade (62.0% versus 90.6%) and grade ≥3 (16.5% versus 50.2%) treatment-related adverse events than chemotherapy.ConclusionsLong-term results (>2 years' follow-up) were consistent with those of previously reported analyses, demonstrating continued clinical benefit of pembrolizumab over chemotherapy for efficacy and safety for treatment of locally advanced/metastatic, platinum-refractory UC.Trial registrationClinicalTrials.gov: NCT02256436

Genetic and biochemical analyses of chromosome and plasmid gene homologues encoding ICL and ArCP domains in Vibrioanguillarum strain 775

Anguibactin, the siderophore produced by Vibrio anguillarum 775 is synthesized from 2,3-dihydroxybenzoic acid (DHBA), cysteine and hydroxyhistamine via a nonribosomal peptide synthetase (NRPS) mechanism. Most of the genes encoding anguibactin biosynthetic proteins are harbored by the pJM1 plasmid. In this work we report the identification of a homologue of the plasmid-encoded angB on the chromosome of strain 775. The product of both genes harbor an isochorismate lyase (ICL) domain that converts isochorismic acid to 2,3-dihydro-2,3-dihydroxybenzoic acid, one of the steps of DHBA synthesis. We show in this work that both ICL domains are functional in the production of DHBA in V. anguillarum as well as in E. coli. Substitution by alanine of the aspartic acid residue in the active site of both ICL domains completely abolishes their isochorismate lyase activity in vivo. The two proteins also carry an aryl carrier protein (ArCP) domain. In contrast with the ICL domains only the plasmid encoded ArCP can participate in anguibactin production as determined by complementation analyses and site-directed mutagenesis in the active site of the plasmid encoded protein, S248A. The site-directed mutants, D37A in the ICL domain and S248A in the ArCP domain of the plasmid encoded AngB were also tested in vitro and clearly show the importance of each residue for the domain function and that each domain operates independently.

Open radial artery harvesting better preserves endothelial function compared to the endoscopic approach

OBJECTIVES: Both the open and endovascular techniques are commonly used for harvesting the radial artery (ORAH and ERAH, respectively), and yet, very little is known about the effects of these 2 techniques on endothelial integrity and function of the radial artery (RA). The aim of this study was to assess the endothelial integrity and function of RA harvested using the 2 approaches. METHODS: Two independent surgical teams working in the same institution routinely use the RA for coronary artery bypass grafting exclusively employing either ORAH or ERAH. Thirty-nine consecutive patients were enrolled in this comparative study. Endothelial function after ORAH or ERAH was assessed by using the wire myograph system. The integrity of the RA endothelium was evaluated by immunohistochemical staining for erythroblast transformation specific-related gene. RESULTS: The vasodilation in response to acetylcholine was significantly higher in RA harvested with ORAH (P ≤ 0.001 versus ERAH). Endothelial integrity was not different between the 2 groups. CONCLUSIONS: ORAH is associated with a significantly higher endothelium-dependent vasodilation. Further investigation on the potential implications of these findings in terms of graft spasm and patency as well as clinical outcomes are needed

Aerothermodynamic Analysis of a Reentry Brazilian Satellite

This work deals with a computational investigation on the small ballistic reentry Brazilian vehicle SARA (acronyms for SAt\'elite de Reentrada Atmosf\'erica). Hypersonic flows over the vehicle SARA at zero-degree angle of attack in a chemical equilibrium and thermal non-equilibrium are modeled by the Direct Simulation Monte Carlo (DSMC) method, which has become the main technique for studying complex multidimensional rarefied flows, and that properly accounts for the non-equilibrium aspects of the flows. The emphasis of this paper is to examine the behavior of the primary properties during the high altitude portion of SARA reentry. In this way, velocity, density, pressure and temperature field are investigated for altitudes of 100, 95, 90, 85 and 80 km. In addition, comparisons based on geometry are made between axisymmetric and planar two-dimensional configurations. Some significant differences between these configurations were noted on the flowfield structure in the reentry trajectory. The analysis showed that the flow disturbances have different influence on velocity, density, pressure and temperature along the stagnation streamline ahead of the capsule nose. It was found that the stagnation region is a thermally stressed zone. It was also found that the stagnation region is a zone of strong compression, high wall pressure. Wall pressure distributions are compared with those of available experimental data and good agreement is found along the spherical nose for the altitude range investigated.Comment: The paper will be published in Vol. 42 of the Brazilian Journal of Physic

Upward Planar Morphs

We prove that, given two topologically-equivalent upward planar straight-line drawings of an $n$-vertex directed graph $G$, there always exists a morph between them such that all the intermediate drawings of the morph are upward planar and straight-line. Such a morph consists of $O(1)$ morphing steps if $G$ is a reduced planar $st$-graph, $O(n)$ morphing steps if $G$ is a planar $st$-graph, $O(n)$ morphing steps if $G$ is a reduced upward planar graph, and $O(n^2)$ morphing steps if $G$ is a general upward planar graph. Further, we show that $\Omega(n)$ morphing steps might be necessary for an upward planar morph between two topologically-equivalent upward planar straight-line drawings of an $n$-vertex path.Comment: Appears in the Proceedings of the 26th International Symposium on Graph Drawing and Network Visualization (GD 2018) The current version is the extended on

On the Globular Cluster IMF below 1 Solar Mass

(Abridged) Accurate luminosity functions (LF) for a dozen globular clusters have now been measured at or just beyond their half-light radius using HST. They span almost the entire cluster main sequence below ~ 0.75 Msolar. All these clusters exhibit LF that rise continuously from an absolute I magnitude M_I ~ 6 to a peak at M_I ~ 8.5-9 and then drop with increasing M_I. Transformation of the LF into mass functions (MF) by means of the most recent mass luminosity relations that are consistent with all presently available data on the physical properties of low mass, low metallicity stars shows that all the LF observed so far can be obtained from MF having the shape of a log-normal distribution with characteristic mass m_c=0.33 +/- 0.03 Msolar and standard deviation sigma = 1.81 +/- 0.19. After correction for the effects of mass segregation, the variation of the ratio of the number of higher to lower mass stars with cluster mass or any simple orbital parameter or the expected time to disruption recently computed for these clusters shows no statistically significant trend over a range of this last parameter of more than a factor of 100. We conclude that the global MF of these clusters have not been measurably modified by evaporation and tidal interactions with the Galaxy and, thus, should reflect the initial distribution of stellar masses. Since the log-normal function that we find is also very similar to the one obtained independently for much younger clusters and to the form expected theoretically, the implication seems to be unavoidable that it represents the true stellar IMF for this type of stars in this mass range.Comment: Accepted for publication in The Astrophysical Journal. Contains 28 pages with 6 figure

Seeing two faces together: preference formation in humans and rhesus macaques

Humans, great apes and old world monkeys show selective attention to faces depending on conspecificity, familiarity, and social status supporting the view that primates share similar face processing mechanisms. Although many studies have been done on face scanning strategy in monkeys and humans, the mechanisms influencing viewing preference have received little attention. To determine how face categories influence viewing preference in humans and rhesus macaques (Macaca mulatta), we performed two eye-tracking experiments using a visual preference task whereby pairs of faces from different species were presented simultaneously. The results indicated that viewing time was significantly influenced by the pairing of the face categories. Humans showed a strong bias towards an own-race face in an Asian–Caucasian condition. Rhesus macaques directed more attention towards non-human primate faces when they were paired with human faces, regardless of the species. When rhesus faces were paired with faces from Barbary macaques (Macaca sylvanus) or chimpanzees (Pan troglodytes), the novel species’ faces attracted more attention. These results indicate that monkeys’ viewing preferences, as assessed by a visual preference task, are modulated by several factors, species and dominance being the most influential

Keep looking ahead? Re-direction of visual fixation does not always occur during an unpredictable obstacle avoidance task

Visual information about the environment, especially fixation of key objects such as obstacles, is critical for safe locomotion. However, in unpredictable situations where an obstacle suddenly appears it is not known whether central vision of the obstacle and/or landing area is required or if peripheral vision is sufficient. We examined whether there is a re-direction of visual fixation from an object fixated ahead to a suddenly appearing obstacle during treadmill walking. Furthermore, we investigated the temporal relationship between the onset of muscle activity to avoid the obstacle and saccadic eye and head movements to shift fixation. Eight females (mean SD; age = 24.8 2.3 years) participated in this experiment. There were two visual conditions: a central vision condition where participants fixated on two obstacles attached to a bridge on the treadmill and a peripheral vision condition where participants fixated an object two steps ahead. There were two obstacle release conditions: only an obstacle in front of the left foot was released or an obstacle in front of either foot could be released. Only trials when the obstacle was released in front of the left foot were analyzed such that the difference in the two obstacle conditions was whether there was a choice of which foot to step over the obstacle. Obstacles were released randomly in one of three phases during the step cycle corresponding to available response times between 219 and 462 ms. We monitored eye and head movements along with muscle activity and spatial foot parameters. Performance on the task was not different between vision conditions. The results indicated that saccades are rarely made (< 18% of trials) and, when present, are initiated ∼ 350 ms after muscle activity for limb elevation, often accompanied by a downward head movement, and always directed to the landing area. Therefore, peripheral vision of a suddenly appearing obstacle in the travel path is sufficient for successful obstacle avoidance during locomotion: visual fixation is generally not re-directed to either the obstacle or landing area

A semi-parametric approach to estimate risk functions associated with multi-dimensional exposure profiles: application to smoking and lung cancer

A common characteristic of environmental epidemiology is the multi-dimensional aspect of exposure patterns, frequently reduced to a cumulative exposure for simplicity of analysis. By adopting a flexible Bayesian clustering approach, we explore the risk function linking exposure history to disease. This approach is applied here to study the relationship between different smoking characteristics and lung cancer in the framework of a population based case control study